Encyclopedia
Please note this is a comparison between Version 1 by Vasile Valeriu Lupu and Version 2 by Lindsay Dong.
Heart failure (HF) is a worldwide health problem with important consequences for the overall wellbeing of affected individuals as well as for the healthcare system. Numerous pieces of evidence have demonstrated that the associated gut microbiota represent an important component of human physiology and metabolic homeostasis, and can affect one’s state of health or disease directly, or through their derived metabolites. The advances in human microbiome studies shed light on the relationship between the gut microbiota and the cardiovascular system, revealing its contribution to the development of heart failure-associated dysbiosis. HF has been linked to gut dysbiosis, low bacterial diversity, intestinal overgrowth of potentially pathogenic bacteria and a decrease in short chain fatty acids-producing bacteria. An increased intestinal permeability allowing microbial translocation and the passage of bacterial-derived metabolites into the bloodstream is associated with HF progression. A more insightful understanding of the interactions between the human gut microbiome, HF and the associated risk factors is mandatory for optimizing therapeutic strategies based on microbiota modulation and offering individualized treatment.
- heart failure
- gut microbiota
- metabolites
- dysbiosis
- immune modulation
1. Introduction
Heart failure (HF) represents a worldwide health problem with significant associated healthcare costs, morbidity and mortality [1]. It is the final stage that results from cardiac structural and functional damage and subsequent imbalances in the compensatory mechanisms and pathogenic processes [2]. HF can take an acute form, correlated with several inflammatory markers and can also appears as a chronic disease, characterized by an altered inflammatory status associated with pro-inflammatory mediators that are considered essential in HF pathogenesis [3].
The bidirectional communication between gut microbiota and extra-intestinal organs has been intensively studied during the last two decades, leading to a better comprehension of the pathophysiological underlying mechanisms and offering a new characterization of HF clinical features, novel risk factors to be taken into account, new diagnostic tools and new therapeutic options [4][5][6][4,5,6].
2. Gut-Associated Microbiome Composition and Function in Healthy Individuals
The human gut microbiome is considered to be an organ on its own with major interactions within the human organism, playing an active role in various immunological, neuronal, metabolic and endocrine responses [7][13]. The highest concentration and diversity of microorganisms from the human body lies in the gastrointestinal tract, consisting of more than 500 distinct species of bacteria, viruses, fungi and protozoa [8][9][14,15]. The GI microbiota are represented by five primary bacterial phyla: the Firmicutes (synonym Bacillota) and Bacteroides (synonym Bacteroidota) phyla predominate the microbiome and represent more than 90% of total bacterial communities, while the Proteobacteria (synonym Pseudomonadota), Actinobacteria (synonym Actinomycetota), and Verrucomicrobia phyla are represented in smaller proportions [7][10][13,16]. Although the Bacillota phylum consists of more than 200 different genera such as Bacillus, Lactobacillus, Enterococcus, Ruminococcus and Clostridium, and the Clostridium genus represents 95% of the phylum. The Bacteroidota phylum is predominated by the Prevotella and Bacteroides genera. The Actinomycetota phylum is significantly less abundant than Bacteroidota phylum and the Bifidobacterium genus is its main representative [11][17]. The microbiome is not inherited, but acquired, and its composition is changing through different stages of each individual’s life, with a unique composition and microbial diversity [12][13][19,20]. Its development starts early, in prenatal life, and continues during birth and through senescence [14][15][21,22]. The following interfere with microbiome composition, leading the way to health or disease: sex; genetics; the mother’s influence during pregnancy and birth; feeding practices in early childhood; dietary habits; antibiotics; tobacco and alcohol use; a sedentary lifestyle associated with the socioeconomic conditions; household pets; pollution; and geographical distribution [9][14][15][16][17][15,21,22,23,24]. Whereas each individual’s gut microbiota are characterized by a specific combination of bacterial species, due to inter-individual and intra-individual variations throughout human life, the human gut microbiota’s functions are highly preserved between individuals [7][13]. In addition to one’s genetic susceptibility, the diversity of the microbiome’s composition plays a key role in each individual’s personalized response to different environmental exposures such as diet, xenobiotics and medical treatments [2]. The GI mucosa represents the site of the human–external environment interaction. The GI microbiota and the intestinal barrier have bidirectional communication and form a complex network influencing the human state of health and disease [8][14]. Besides its function as an organ used for digestion and absorption, the GI tract acts as an immune organ, the human body’s largest immune organ [18][25]. “Healthy” gut microbiota have the capacity for: preserving the stability of the intestinal wall and its barrier function; tight epithelial junctions and a normal mucosal immunity; and preventing pathogen proliferation [2]. The gut-associated microbiota can regulate the inflammatory response directly, inducing either innate or adaptive immune responses, or it can alter the immune cells’ function using active metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMA-O) and indoleacetic acid (IAA) [19][20][21][26,27,28].3. Impaired Gut Barrier Function and Inflammation in Heart Failure
The “gut hypothesis” in HF suggests that there is a strong relationship between the gut microbiota, its metabolites and HF pathogenesis, as illustrated in Figure 1 [2][22][2,31]. Although this bidirectional communication is not fully understood, evidence indicates that this bacterial translocation appears in HF as a consequence of various mechanisms leading to structural and functional alterations of the GI tract, from splanchnic congestion to the host’s immunological defense system [23][7]. Figure 1.
Concept of the gut–heart axis adapted to HF.
Available data suggest that the alteration of the structure and the function of the gut comes as a consequence of the microcirculatory perturbation that appears in HF patients [24][8]. In these patients, mainly in a decompensated form of the disease, the disruption of the normal composition of the gut microbial communities comes as a result of the intestinal hypoperfusion, that leads to changes in local pH and gut luminal hypoxia [25][32]. There is evidence of a disrupted intestinal epithelial function associated with HF: an alteration that seems to be the result of a reduced intestinal perfusion and ischemia [13][26][20,33].
Besides intestinal wall edema, HF is characterized by a reduction in the absorptive capacity and an increase in the epithelial permeability of the gut, facilitating the passage of several intestinal bacterial and/or endotoxins, such as lipopolysaccharides (LPS), from the gut to the systemic bloodstream [27][28][9,34]. LPS is a biologically active constituent of the Gram-negative bacterial wall with potential immunostimulatory activity by using the Toll-like receptor 4 (TLR4) pattern recognition receptor [29][35]. In HF patients, high LPS concentrations found in the hepatic veins sustain the hypothesis of an intestinal translocation process of gut microbes [30][36].
The endotoxin intestinal absorption stimulates an increase in systemic inflammatory cytokines levels [13][20]. According to current data, HF appears to be correlated with a chronic state of inflammation that can be induced or accelerated by this microbial translocation, indirectly affecting cardiomyocytes’ normal function [31][37]. It seems that increased levels of circulating cytokines correspond to more severe clinical symptoms and to a worse prognosis in HF patients’ survival [32][33][38,39]. Serum levels of TNF-alpha, IL-1 and IL-6 of HF patients are directly influenced by the amount of existing LPSs, currently thought to be leading elements of a hyperinflammatory condition [18][25]. While in decompensated HF patients, LPS levels appear to be directly associated with systemic inflammation markers, and they decrease following HF recompensation. Treatment administration is not always followed by a decrease in plasma cytokine levels, suggesting a sustained effect as the disease progresses [13][34][20,40].
4. Dysbiosis in Heart Failure
Gut microbiota, as the most important active components in the intestinal microecosystem, have been shown to have a strong influence on HF. Besides the correlation with inflammation and increased intestinal permeability, an analysis using fluorescence in situ hybridization described the presence of bacterial overgrowth as mucosal biofilm and an increased bacterial adhesion in the sigmoid colon mucus of HF patients. The increased intestinal juxta mucosal bacterial biofilm has been correlated with an amplified immunoglobulin A–anti-LPS response [13][26][20,33].
In stable chronic HF with reduced ejection fraction (HFrEF) patients, an increased level of pathogenic bacteria such as Salmonella, Shigella, Campylobacter and Yersinia species, as well as yeasts including Candida species, have been reported as assessed by microbial culture methods; their levels being correlated with HF severity [35][10]. Consistent with these results, there is evidence that the Escherichia/Shigella genus is increased in the same patient known with HF, during its decompensated compared to the compensated phase of disease [36][48].
Using 16S rRNA gene sequencing Sun and colleagues [37][11] analyzed fecal samples of patients with severe forms of chronic HF and compared the results with the one obtained from healthy controls. They reported reduced alpha diversity in chronic HF patients and important differences in beta diversity between the two groups. Bacillota phylum was found to be dominating the chronic HF patient’s fecal microbiota, but in smaller levels than the controls. Pseudomonadota and Actinomycetota, however, were reported to be more abundant than in the control samples. Moreover, Pseudomonadota phylum was the second most abundant phylum found in severe chronic HF patients instead of Bacteroidota phylum. Pseudomonadota phylum is composed of Gram-negative bacteria, mainly pathogens, and is thought to be a microbial signature of dysbiosis in gut bacterial communities [37][11].
D. longicatena is a bacterium that produces acetic acid, an SCFA, as a fermentation product. However, acetate can be further used as a substrate in order to generate butyrate [38][62]. Eubacterium rectale, another butyrate producer bacterium, was identified at increased levels in gut mucosal biofilms of HF patients by Sandek and colleagues [26][33]. In contrast, another study by Kamo et al. [24][8] reported decreased levels of the bacteria as characterizing HF [24][8]. Faecalibacterium prausnitzii, another butyrate-producing commensal bacteria with anti-inflammatory properties, was found to be decreased in abundance in HF patients, negatively affecting the intestinal permeability [39][40][41][58,63,64]. Butyrate-producing bacteria are essential for the state of well-being of each individual, as butyrate is used as an energy source for intestinal epithelial cells, and it regulates the integrity of the epithelial barrier and suppresses the intestinal and extra-intestinal inflammation [42][43][65,66]. The decreased levels of F. prausnitzii and increase in Ruminococcus gnavus were found to be important characteristics of gut microbiota in chronic HF patients [44][60].
